The present invention relates to compositions and methods for use in the transient suppression of the inflammatory response by suppressing plasma levels of tissue necrosis factor-alpha and increasing plasma levels of interleukin-6.
When an injury occurs, cell damage initially comes from the precipitating event, such as a cut, resulting in ruptured cells and severed or crushed capillaries and other blood vessels. The interruption of blood flow results in anoxia, causing the death of additional cells. The wound site quickly fills with dead and dying cells, extracellular substances (collagen, elastic fibers, fat and ground substances), extravasated blood, and possibly bacteria and viruses introduced during the injury.
Tissue damage is not restricted to the initial area of injury, and may increase over the next several hours or days as a result of the release of lysomal enzymes from the injured cells or as a consequence of inflammation (swelling) and/or infection. (See Reese et al., Role of Fibronectin in Wound Healing, the subject matter of which is hereby incorporated by reference.) The inflammatory response is one of the normal stages of wound healing, and is necessary for subsequent phases of healing.
Inflammation is a vital process necessary for an organism to survive an external insult, such as a wound or burn. However, if unchecked, inflammation can have harmful consequences. For example, many chronic and even life-threatening disorders, such as asthma, rheumatoid arthritis, lung fibrosis, peritoneal adhesions, hypersensitivity and autoimmune diseases are a result of an uncontrolled inflammatory response. An unresolved inflammation in the lung resulting from bacterial infection (i.e., pneumonia) may eventually lead to extensive tissue damage and a chronic lung abscess. Inflammation of the peritoneal cavity, for example, and the resulting adhesions following abdominal surgery is a major cause of infertility in women. Asthma is an often life-threatening disorder which results from an inadvertently stimulated inflammatory response in the lungs. An excessive inflammatory response can cause extensive swelling, which can lead to additional injury as a result of anoxia. Pain results from a combination of kinins and the effect of lysozymes and pressure from the swelling on nerve endings. Unchecked, the inflammatory response can set off a neural feedback loop and cause hyperalgesia, a phenomenon in which the surrounding area of injury remains painful. Accordingly, there is a great interest in the medical community to develop anti-inflammatory agents.
Many known anti-inflammatory compositions reduce the inflammatory response, but are also immunosuppressive. For example, corticosteroids are potent anti-inflammatory agents, but are associated with T-cell suppression and increased infections. Interleukin-10 (as well as IL-4 and IL-3 to lesser extents) are broadly acting anti-inflammatory agents, but are associated with decreased cell mediated immune functions.
It would be advantageous to provide compositions and methods which provide protection from adverse effects associated with inflammation, preferably without unnecessary immunosuppression. The present invention provides such compositions and methods.
Compositions and methods for providing protection from adverse effects associated with inflammation are disclosed. The compositions and methods can suppress plasma concentrations of tissue necrosis factor-alpha (TNF-xcex1) while increasing plasma concentrations of interleukin-6 (IL-6).
The compositions include non-interlinked particles of bioactive glass with a size less than about 20 xcexcm, alone or in combination with an additional anti-inflammatory agent, and optionally include other therapeutic agents. Formulations including the composition and a suitable carrier, preferably for oral, intramuscular, intraperitoneal or intravenous administration, are also disclosed.
The composition can be administered orally, intramuscularly, intraperitoneally or intraveneously to provide systemic relief from the adverse effects associated with inflammation, for example, the effects of excess TNF-xcex1.